We are investigating mechanisms by which acupuncture regulates cardiovascular function, focusing on its modulation of elevated blood pressure (BP). Electroacupuncture (EA) is capable of lowering acute and chronic elevations in BP and alleviating demand-induced myocardial ischemia. Acupuncture's actions are slow in onset, but the duration of action is prolonged. We have been funded previously to study neural mechanisms underlying acupuncture's cardiovascular effects. Although these studies have shown that both EA and manual acupuncture (MA) applied at acupoints overlying somatic afferent nerves attenuate cardiovascular sympathoexcitatory responses, the mechanisms by which various forms of acupuncture application activate sensory nerve fibers to lower elevated BP are largely unknown. In this regard, although EA and MA activate sensory nerves through electrical and mechanical stimulation, it is unclear whether these modalities stimulate sensory afferent nerves and their perikarya in dorsal root ganglia through direct depolarization of fibers in passage or through a chemical intermediate mediated by a receptor specific mechanism, such as transient receptor potential vanilloid type-1 (TRPV1) or ATP purinergic receptors. Our studies also have demonstrated that, following stimulation of sensory nerves, EA lowers reflex elevations in BP through opioids by modulating presympathetic activity in the rostral ventrolateral medulla (rVLM), a brain stem nucleus that importantly controls sympathetic outflow and hence cardiovascular function. However, it is unclear if opioids act alone or mediate the actions of other cardiovascular-suppressing neuromodulators like adenosine or ?-amino butyric acid (GABA) to facilitate the action of acupuncture in lowering elevated BP during cardiovascular excitatory responses as well in sustained hypertension. Additionally, there is no information available on the role of opioids and other neurotransmitters in lowering elevated BP with acupuncture applied at locations other than somatic acupoints, like auricular acupuncture (AA). In this respect, manual and electrical AA applied at the heart point in the ear, which likey activates vagal afferent nerves projecting to the medulla, is used empirically to manage elevated BP. However, medullary mechanisms underlying AA's hypotensive actions remain unknown. The central hypothesis of this application is that acupuncture at somatic and cranial vagal nerve acupoints lowers elevated BP by modulating rVLM presympathetic activity through opioid- mediated mechanisms, by stimulating sensory receptors (MA) or thin fiber axons in passage (EA). The present grant focuses on four new areas: 1) electrical and mechanical-chemical sensory neural mechanisms by which EA and MA inhibit cardiovascular function; 2) the role of rVLM adenosine in opioid mediation of acupuncture inhibition of excitatory cardiovascular reflex responses; 3) acupuncture's action in lowering BP in sustained hypertension through medullary enkephalins and adenosine and 4) medullary mechanisms of auricular acupuncture in modulating elevated BP through actions of opioids and GABA. Anatomical, biochemical, physiological, electrophysiological, pharmacological and molecular approaches will be used in the proposed studies that are highly relevant to patients with hypertension and sympathetic hyperactivity, who have the potential to benefit from clinical acupuncture.